Transfusion of blood is one of the oldest and most widely used clinical interventions. In 2020 the World Health Organisation reported that globally 118.5 million blood donations had been collected worldwide. This blood will be used to provide life-saving transfusion support for millions of individuals with a wide range of medical conditions. To ensure the safety of each blood transfusion it is common policy to identify and ensure compatibility between the ABO and RhD antigens of both donor and recipient. Although this policy prevents the majority of adverse haemolytic transfusion reaction’s (HTR), approximately 3% of recipients become sensitised following an immune reaction to a non-self blood group antigen after a single transfusion episode. This proportion can rise dramatically in patients requiring frequent transfusion support, with immunisation rates as high as 60% being reported for some haemoglobinopathy patients. Sensitisation to non-self red blood cell (RBC) antigens confers a lifetime risk of HTRs, which from 2013 through 2017 were responsible for 17% (32 of 185) and 6% (7 of 110) of transfusion-related deaths reported to the US Food and Drug Administration and Serious Hazards of Transfusion UK, respectively. Furthermore, sensitisation can render transfusion-dependent patients non-transfusable and cause haemolytic disease in pregnancy which is potentially life-threatening to the fetus. A more precise blood matching policy will reduce sensitisation rates, however, adoption of this is resisted because of perceived logistical challenges, donor typing costs, and the lack of evidence from large scale clinical trials that reducing sensitisation rates results in health gains. Antibody-based haemagglutination tests are the current gold standard for RBC antigen typing; however, reliable reagents and high-throughput techniques are not available for all clinically relevant antigens. DNA-based tests have been used to overcome these limitations, and a range of in-house and commercial assays have been developed for donor genotyping. However, due to the limited number of antigens typed for and the low throughput capacity of these assays, they have not been widely applied to blood donor typing. Advances in the technologies used for genome-wide genotyping and sequencing have substantially reduced the cost of generating genetic variation data at population scale. Multiple studies have demonstrated that it is possible to extract antigen typing information from the data produced by these technologies, indicating that they could be used to deliver genomics-based precision transfusion medicine to the patient bedside. However, the same studies also highlight a series of challenges that would have to be overcome before these technologies could be safely integrated into the clinical laboratory. In this thesis, I will present the work that has been done to overcome some of the issues surrounding the interpretation of blood cell antigen typing from genomic data and the development of a universal donor genotyping platform which can be used by blood supply organisations worldwide to implement of a policy of precision transfusion medicine.
Transfusion Medicine, Haematology, Genetics, Genomics
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